OB-24, a novel selective and potent HO-1 inhibitor, induces a wide spectrum anti-tumor activity in vitro and in vivo and synergizes with chemotherapy drugs
Bibliographic record
Abstract
C82 Mortality from cancer is attributed primarily to the dissemination of primary tumor cells to distant organs, where only limited therapeutic options are available for patients. The new shift toward targeted therapies for metastatic & drug resistant cancer have provided encouraging clinical results and reinforced the effectiveness of targeting cancer-associated targets. Here, we report the anti-tumor and anti-metastatic activity of a novel class of targeted agents that interfere with heme oxygenase 1 (HO-1). HO-1 is a highly-inducible 32 kDa member of the stress protein superfamily that catalyzes the oxidative degradation of heme to biliverdin. We have identified HO-1 to be implicated in the regulation of growth and survival of a large panel of human cancer cell lines. Furthermore, HO-1 was found to be differentially expressed in human cancer tissues, including prostate carcinoma at different stages of progression. OB-24, a novel substituted imidazole, was found to have highly selective inhibitory activity toward HO-1 but not HO-2 enzymatic activity, based on the IC50 inhibitory values for HO-1 (rat spleen) and HO-2 (rat brain), enzymes, respectively. OB-24 was well tolerated by mice at multiple doses up to 100 mg/kg dose when given by intraperitonal as well as intravenous routes. Antitumor activity was seen in the PC-3 prostate carcinoma model, SKMEL-24 melanoma model, HCT-116 colorectal carcinoma model and OVCAR-3 ovarian carcinoma model. The activity of OB-24 in these models was equal to or higher than that of the standard chemotherapy agents: 5-FU, Taxol, Dacarbazine, and Cisplatin. In the PC-3 model, OB-24 showed a dramatic activity (approximately 90% inhibition compared to vehicle alone) when combined with Taxol. Immunohistochemistry studies clearly indicate that the activity of OB-24 combined with taxol significantly inhibited lung metastasis formation. Furthermore, CD-31 staining revealed that OB-24-treated tumors exhibited a significant reduction in vascularization. Similar results on alternative preclinical models will be presented. In summary, our data support the clinical therapeutic utility of selective HO-1 inhibitors for the treatment of advanced and chemotherapy refractory cancers.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".